Individuals suffering from chronic pain often have psychiatric comorbidities. Among those with chronic migraine, for instance, approximately 9% fit into the bipolar spectrum.1 This paper discusses a representative case of a patient with chronic migraine and bipolar disorder as well as epilepsy and irritable bowel syndrome.

Sample Case: Bipolar, Chronic Migraine, Epilepsy, and IBS-D

Caitlin is a 28-year-old female who has experienced frequent depressive states since age 14. She finally was diagnosed at age 26 to be on the mild end of the bipolar spectrum (DSM-5: Other Specified Bipolar and Related Disorder: 296.89). She presents with her depression in remission and is on quetiapine 50mg and lamotrigine 100mg, each once per day.

The patient has moderate chronic migraine and describes daily mild to moderate headache. She has a moderate migraine twice weekly, and a severe migraine attack once a month. She takes 8 OTC aspirin / acetaminophen(paracetamol) / caffeine tablets (Excedrin) daily.

Caitlin reports significant occipital and neck pain. She has had tonic-clonic epilepsy since age 12. Her seizures are infrequent, and since being placed on lamotrigine she has had no further seizures. Caitlin’s IBS, primarily with diarrhea (IBS-D), is considered moderate.

Work-up was negative, including brain MRI, routine blood tests (including thyroid), and neurology examination.

What Additional History May be Helpful?

In this case scenario, relevant factors to consider and further investigate include:

  • frequency and severity of the headaches
  • past response to medications and family history of response (a family history of medication response brings in the “placebo by proxy” and “nocebo by proxy” responses)
  • potential sensitivities or side effects to medications
  • psychiatric comorbidities
  • medical comorbidities
  • GI issues (in this case, IBS-D)
  • any complaints related to sleep, fatigue, or insomnia
  • the patient’s job requirements, social support, and any financial/insurance concerns that may impact her treatment
  • patient preference for medication (eg, they may not wish to take daily medication, or may request to use natural remedies)

In addition, a history of the specifics of this patient’s depression would be helpful. The details of her moods, hypomanic symptoms, triggers, etc, are important if an adjustment to psychiatric medication is deemed appropriate.2

Is the Patient Suffering from Medication Overuse Headache?

It is also worth considering whether the patient may have medication overuse headache (MOH) which is often conflated with medication overuse (MO). Medication overuse is arbitrarily viewed as consuming certain abortive medications (eg, combination analgesics, triptans, opioids, butalbital compounds) at least 11 days per month. If patients simply take NSAIDS, MO is defined as consuming the NSAIDS at least 15 days per month.

A determination of MOH is more complex as it tends to be poorly defined and over-diagnosed.3 To determine whether MOH is present, a careful history has to be taken as to the effect the drug had on the person’s headaches. The drug (in this case, Excedrin) must be withdrawn to see if the headaches improve. Caitlin reports taking 8 Excedrin on a daily basis, each of which contains 65 mg of caffeine. It would be helpful to determine how much additional caffeine she consumes.

I would attempt to limit her caffeine intake to 150 or 200 mg daily. While small amounts of caffeine help many patients, other migraineurs cannot tolerate even minimal amounts.

(Editor’s Note: The author further describes the variables that may drive clinical decision-making in Deconstructing the Art of Headache Medicine in our sister publication Practical Pain Management.)

Psychiatric Drug Options & Considerations

When treating chronic migraine, there are two main categories of medications: daily preventives and abortives. Not all patients require preventive approaches for their headaches. For patients with psychiatric illness, such as the patient presented here, I often prescribe the psychiatric medications known to help with migraine pain and related symptoms.

Tricyclic Antidepressants

Without the diagnosis of the bipolar spectrum, tricyclic antidepressants might be helpful as these can also help to alleviate other symptoms, such as IBS-D.  Which tricyclic to use depends on the patient’s age, sleep, fatigue, and weight. For example:

  • amitriptyline – and its milder metabolite, nortriptyline – can be helpful when treating sleep and headaches, but weight and anticholinergic side effects often limit use. Both drugs raise both serotonin and norepinephrine.
  • doxepin is not quite as effective for the headache but may be better tolerated due to fewer anticholinergic effects. Due to prominent antihistaminic effects, doxepin is often used for insomnia.
  • protriptyline is not usually sedating and does not cause weight gain, but has limited efficacy for headache. This drug is primarily a norepinephrine reuptake inhibitor but has mild serotonergic effects as well. Protriptyline can cause severe anticholinergic effects.
  • imipramine is occasionally helpful and works similarly to amitriptyline. Desipramine (which primarily raises norepinephrine) is milder and comes with less severe anticholinergic and sedating effects. However, desipramine is not as effective for headache or pain.


When tricyclics are not appropriate, and for those not in the bipolar spectrum, SNRIs may be useful as well.

  • duloxetine is the most commonly used SNRI for pain.
  • venlafaxine (and desvenlafaxine) are also helpful for some patients.

Note that venlafaxine and desvenlafaxine are considered SNDRIs but, at low doses, they essentially act as SSRIs. With medium doses, norepinephrine levels are enhanced, and at higher doses, dopamine is increased. Upon discontinuation, withdrawal may be more severe with the SNRIs.

Returning to our patient case, since Caitlin fits into the bipolar spectrum, antidepressants and the tricyclics mentioned above should be avoided. For those in the bipolar spectrum, antidepressants often either do not help or increase the mind racing and cycling. There are exceptions where they may be beneficial, particularly if the patient is on a mood stabilizer.


Atypical or second-generation antipsychotics may help to manage Caitlin’s moods but they could impart a slight risk of increasing her seizure frequency.

The first-generation antipsychotics are associated with slightly less epilepsy risk than the atypical antipsychotics.4 Antipsychotics do not usually prevent migraine. Quetiapine is often used in migraine patients who suffer from severe anxiety and/or insomnia (doses are usually kept as low as possible). For those with extrapyramidal side effects due to an antipsychotic, switching to clozapine or quetiapine may be the best alternative. Clozapine may be the worst offender regarding seizure risk. While quetiapine or olanzapine have occasionally been helpful for aborting a migraine, there have not been adequate controlled trials to advocate their use as an abortive.

(Editor’s Note: See our clinical primer on first- and second-generation antipsychotics and a clinical update on bipolar depression medication approaches.)

In comparison, antidepressants do not substantially increase seizure risk in low or normal doses. SSRIs, SNRIs, and tricyclics may actually lower the risk slightly. However, the antidepressant bupropion (at 300 mg a day or more) can increase the risk for a seizure, as can clomipramine.4

Migraine Medication Options

The patient’s past history of response to medications can help guide possible treatment choices for migraine management. In Caitlin’s case, her family’s response to medications may be useful.  Other important factors to discuss include her quality of sleep (particularly insomnia), energy level, and job requirements.2

If I suggest the anticonvulsant topiramate to Caitlin, and her mother shares, “That was the worst medication, I did poorly on it,” then it would likely not be a good choice for Caitlin (the “nocebo by proxy” response). Likewise, if her father has a history of depression and experienced severe “bipolar” side effects from tricyclic antidepressants (often used for migraine), that is suggestive of a bipolar family history. In the author’s opinion, genetic factors should be considered regarding medication response.

Patient preferences regarding medications certainly contribute to our choices as well.  Whether to use daily migraine preventives depends upon the frequency and severity of headache, plus comorbidities. If she states that the migraines are severe and debilitating, and Caitlin is willing to take a daily medication, I would employ a preventive approach. Preventives are generally categorized by: natural; beta-blockers/calcium channel blockers/ angiotensin II receptor blockers; antidepressants; anticonvulsants; onabotulinum toxin A injections; and CGRP monoclonal antibody injections.5

Caitlin does not appear to have refractory chronic migraine (a lack of response to three preventive classes) but for those with refractory migraine, one might consider: MAOIs, opioids, ketamine (eg, nasal spray at home), nerve blocks or injections (eg, SPG), muscle relaxants, neuromodulation, daily triptans, or polypharmacy with various preventives.

To address Caitlin’s migraine, as noted, my first priority would be to slowly wean her down on the excessive Excedrin. Ideally, I would want to use migraine-specific abortive medications. The six triptans (eg, sumatriptan, rizatriptan) have 30 years of safety and efficacy behind them. There are tablets, nasal sprays, and injections available as well. A new class, gepants, has emerged as a safe and effective alternative to the triptans. Gepants have few drug interactions and may be used with other abortives – even at the same time. Gepants have no vasoconstrictive effects and appear to be better tolerated than the triptans. Efficacy of the gepants is slightly lower than with the use of triptans.

Many patients in my clinic utilize a number of different abortives, albeit at different times.  These may include an NSAID or OTC medication, a triptan, a gepant, an analgesic, and an antiemetic. I prescribe opioids only as a last resort. For those with severe and prolonged migraine, low doses of corticosteroids often prove useful as well.

Outside of Medication, What Can Clinicians Advise?

At my clinic, we always discuss non-pharmacologic approaches. With migraine patients, I often prescribe vitamin D (average = 2,000U daily). Nature Made is a reliable brand, as it is USP certified. I try to limit their use of other supplements, as most supplements and herbs have not held up to scientific scrutiny.

I have also seen successful patient outcomes when recommending a combination of psychotherapy and physical therapy. Physical therapists are particularly helpful in managing patients’ posterior pain (occipital and cervical) while psychotherapists can guide patients through mindfulness and meditation techniques. Biofeedback is helpful in some cases as well. Meditation may be useful. Massage or acupuncture are occasionally employed.

With Caitlin, I would particularly stress the need for an excellent psychotherapist who can address catastrophizing,6 acceptance, and resilience as they relate to chronic pain – in this case, her chronic migraine.

In conclusion, chronic migraine and psychiatric comorbidities often coexist. There is no adequate algorithm that is useful for these patients. Each person is unique regarding the frequency and severity of the headaches, comorbidities, and daily functioning needs. I aim to guide non-pharmacologic choices toward a patient’s various comorbidities, and minimize medication use, gearing it toward alleviating the comorbid conditions as well as the headache pain. Therapeutic choices always involve a partnership between the provider and the patient.


Last Updated: Jul 14, 2021